TMEM14C is required for erythroid mitochondrial heme metabolism
Yvette Y. Yien, … , Luanne L. Peters, Barry H. Paw
Yvette Y. Yien, … , Luanne L. Peters, Barry H. Paw
Published October 1, 2014; First published August 26, 2014
Citation Information: J Clin Invest. 2014;124(10):4294-4304. https://doi.org/10.1172/JCI76979.
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Research Article Hematology

TMEM14C is required for erythroid mitochondrial heme metabolism

Abstract

The transport and intracellular trafficking of heme biosynthesis intermediates are crucial for hemoglobin production, which is a critical process in developing red cells. Here, we profiled gene expression in terminally differentiating murine fetal liver-derived erythroid cells to identify regulators of heme metabolism. We determined that TMEM14C, an inner mitochondrial membrane protein that is enriched in vertebrate hematopoietic tissues, is essential for erythropoiesis and heme synthesis in vivo and in cultured erythroid cells. In mice, TMEM14C deficiency resulted in porphyrin accumulation in the fetal liver, erythroid maturation arrest, and embryonic lethality due to profound anemia. Protoporphyrin IX synthesis in TMEM14C-deficient erythroid cells was blocked, leading to an accumulation of porphyrin precursors. The heme synthesis defect in TMEM14C-deficient cells was ameliorated with a protoporphyrin IX analog, indicating that TMEM14C primarily functions in the terminal steps of the heme synthesis pathway. Together, our data demonstrate that TMEM14C facilitates the import of protoporphyrinogen IX into the mitochondrial matrix for heme synthesis and subsequent hemoglobin production. Furthermore, the identification of TMEM14C as a protoporphyrinogen IX importer provides a genetic tool for further exploring erythropoiesis and congenital anemias.

Authors

Yvette Y. Yien, Raymond F. Robledo, Iman J. Schultz, Naoko Takahashi-Makise, Babette Gwynn, Daniel E. Bauer, Abhishek Dass, Gloria Yi, Liangtao Li, Gordon J. Hildick-Smith, Jeffrey D. Cooney, Eric L. Pierce, Kyla Mohler, Tamara A. Dailey, Non Miyata, Paul D. Kingsley, Caterina Garone, Shilpa M. Hattangadi, Hui Huang, Wen Chen, Ellen M. Keenan, Dhvanit I. Shah, Thorsten M. Schlaeger, Salvatore DiMauro, Stuart H. Orkin, Alan B. Cantor, James Palis, Carla M. Koehler, Harvey F. Lodish, Jerry Kaplan, Diane M. Ward, Harry A. Dailey, John D. Phillips, Luanne L. Peters, Barry H. Paw

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Figure 7

The heme defect in Tmem14c-deficient MEL cells is complemented by the addition of DP.

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The heme defect in Tmem14c-deficient MEL cells is complemented by the ad...
(A) 55Fe-metabolic labeling of differentiating MEL cells that were treated with either Fe-dextran (Fe) or Fe-dextran with DP (Fe+DP). Fe-dextran with DP supplementation, but not Fe-dextran alone, significantly increased heme synthesis in Tmem14c-deficient (CRISPR and shRNA) cells to similar quantities as untreated control cells. In contrast, Fe-dextran with DP does not complement the heme synthesis defect in Snx3-deficient cells. *P < 0.05. (B) Quantitation of total cellular iron by 55Fe metabolic labeling. Fe-dextran and Fe-dextran with DP supplementation did not significantly alter total cellular iron content in control, Tmem14c-deficient, or Snx3-deficient cells. (C) Proposed model for the function of TMEM14C (brown cylinder) as a PPgenIX transporter, enabling access to PPOX and facilitating synthesis of PPIX and eventually heme in the mitochondria of developing erythroblasts. Heme synthesis enzymes are represented by light blue boxes, while heme and porphyrin intermediates are indicated in dark blue text.